Given that genome sequencing has the potential to identify tens of thousands of variants in every patient sample tested, our GCs are often asked about how we handle incidental findings in our reporting. In this post we’ll explore the different types of possible findings and describe our reporting policies.
Related vs unrelated findings
Let’s start by defining related and unrelated findings.
When a patient’s genome is sequenced, it is compared against a reference or “standard” to identify the variants that are present. Some of the identified variants are relevant to diagnosing the condition for which the patient has sought testing. These are considered to be related findings – because they are believed to be directly related to the patient’s current condition and may provide immediate benefits for the patient related to that condition. Related findings are always reported.
Some of the identified variants may be irrelevant to diagnosing the condition for which the patient has sought testing, but may still have value for medical management and decision making. These are considered to be unrelated findings – because they are not directly related to the patient’s current condition and provide no immediate benefit for the patient related to that condition. Unrelated findings are commonly referred to as incidental findings or secondary findings. In this post we will use incidental findings. Incidental findings may or may not be reported, depending on the type of incidental finding and the patient’s wishes as specified during the informed consent process.
Incidental findings that are not reported
Some types of incidental findings will not typically be reported because they fall outside the scope of the test. Examples of such incidental findings include:
- High frequency risk alleles
- Pharmacogenomic variants in CYP genes related to drug metabolizer status
- Carrier status (heterozygous pathogenic variants in genes associated with autosomal recessive conditions that are not associated with the patient’s reported symptoms)
- Variants for late-onset conditions
Incidental findings that may be reported
Some incidental findings are unavoidable.
Some can simply be deduced from testing, such as discovering non-paternity when testing the parents of a child in trio analysis or discovering that a parent is a carrier for the condition identified in the child.
Other incidental findings are variants in genes that may fit the patient’s clinical phenotype, but are also associated with unrelated or later onset conditions. For example, more than 450 different pathogenic variants have been identified in the LMNA gene, which can cause a wide variety of distinct and disparate diseases involving striated muscle (dilated cardiomyopathy, skeletal myopathies), adipose tissue (lipodystrophy syndromes), peripheral nerve (Charcot-Marie-Tooth neuropathy) or multiple systems with accelerated ageing (progerias). These results would likely be reported because they are integral to testing. The possibility of receiving unavoidable incidental findings should be discussed with the patient and family prior to testing, so they are aware that these results, if present, are likely to be returned to them. If the patient does not wish to receive these results, they can decide not to continue with testing.
Other incidental findings are optional.
These incidental findings are variants in genes that do not fit with the patient’s clinical phenotype and would not typically be reviewed during routine processing of patient samples. They will only be reviewed when a patient has actively selected to opt-in to receiving incidental findings during the informed consent process.
- Findings in the set of 59 genes recommended by the American College of Medical Genetics and Genomics (ACMG)
- Findings in other genes
ACMG recommended genes
The American College of Medical Genetics and Genomics (ACMG) recommends reviewing and reporting pathogenic and expected pathogenic variants in a list of 59 genes. They have recommended this list because the genes are related to conditions that are “actionable”, meaning that there are steps that can be taken to mitigate the onset or severity of the clinical outcome. These genes are primarily related to cancer and cardiac conditions. The list of 59 genes and their associated conditions can be viewed here.
There are additional genes that are not part of the ACMG’s recommended set, but are similar in that they have some associated actionability such as monitoring for possible cardiac implications, increased cancer screening or monitoring of iron levels, have a dietary impact or are diseases for which possible treatment is available (for example, cardiovascular diseases predisposing to sudden cardiac death). Like the genes in the ACMG list, they could impact medical management and decision making. For examples of such genes, see our related post “Medically actionable genes that go beyond the ACMG set of 59”.
For both sets of genes it’s important to be aware that incidental findings are not reported for variants of uncertain significance (VUS).